J Comput Aided Mol Des (2007) 21:145–153 DOI 10.1007/s10822-006-9090-y ORIGINAL PAPER 3D-QSAR study of hallucinogenic phenylalkylamines by using CoMFA approach Zhuoyong Zhang Æ Liying An Æ Wenxiang Hu Æ Yuhong Xiang Received: 4 July 2006 / Accepted: 22 October 2006 / Published online: 4 January 2007 Ó Springer Science+Business Media B.V. 2006 Abstract The three-dimensional quantitative struc- Keywords 3D-QSAR Á Amphetamines Á CoMFA Á ture–activity relationship (3D-QSAR) has been stud- Hallucinogen Á Phenylethylamines ied on 90 hallucinogenic phenylalkylamines by the comparative molecular field analysis (CoMFA). Two conformations were compared during the modeling. Introduction Conformation I referred to the amino group close to ring position 6 and conformation II related to the Hallucinogens are substances that provoke strong amino group trans to the phenyl ring. Satisfactory mental and psychic changes including disorientation, results were obtained by using both conformations. derealization and depersonalization, giving rise to a There were still differences between the two models. variety of abnormal phenomena [1]. In some countries, The model based on conformation I got better statis- they are used as components of drugs. Some people tical results than the one about conformation II. And especially young people show a special interest and this may suggest that conformation I be preponderant may be addicted to these drugs for stimulation and self- when the hallucinogenic phenylalkylamines interact realization effects. And more seriously, hallucinogens with the receptor. To further confirm the predictive may be used to produce terror events by terrorists. To capability of the CoMFA model, 18 compounds with ensure the safety and the peace, strict administration conformation I were randomly selected as a test set and fast monitoring of hallucinogens are required. and the remaining ones as training set. The best Hallucinogens include mainly two categories of CoMFA model based on the training set had a cross- compounds according to their chemical structure. validation coefficient q2 of 0.549 at five components One is phenylalkylamines (phenylethylamines and and non cross-validation coefficient R2 of 0.835, the amphetamines), and the other is indolealkylamines standard error of estimation was 0.219. The model such as tryptamines and lysergic acid diethylamide showed good predictive ability in the external test with (LSD) derivatives .The 5-HT2A receptor is consid- 2 a coefficient Rpre of 0.611. The CoMFA coefficient ered to act as the biological target of these com- contour maps suggested that both steric and electro- pounds [2], however, the three-dimensional structure static interactions play an important role. The contri- of 5-HT2A receptor is not available so far, so most butions from the steric and electrostatic fields were studies are based on homologous compounds. To 0.450 and 0.550, respectively. understand the activity of hallucinogens at molecular level, their quantitative structure–activity relation- ships (QSARs) have been studied and several QSAR models have been established [3–7]. Most of the models were based on quantum chemistry parameters & Z. Zhang ( ) Á L. An Á W. Hu Á Y. Xiang or physical chemistry parameters, and the computa- Department of Chemistry, Capital Normal University, 105 Xisanhuan North, Beijing 100037, P.R. China tion based on quantum chemistry is slow and time- e-mail: [email protected] consuming. 123 146 J Comput Aided Mol Des (2007) 21:145–153 Comparative Molecular Field Analysis (CoMFA) USA) on a personal computer with Pentium IV pro- was developed by Cramer [8], and this method has cessor. Molecular building was done with molecular been well established for ligand-based 3D-QSAR sketch program. Since the crystal structure of DOET studies [9, 10]. It is based upon the calculated energies (4-ethyl-2,5-dimethoxyamphetamine) has been re- of steric and electrostatic interactions between the ported [11], the rest of the molecules were constructed compound and the probe atom placed at the various using DOET as template. Active conformation selec- intersections of a regular 3-D lattice. After this region tion is a key step for CoMFA analysis. Conformation is generated, the results are compared to the pharma- with the lowest energy is not always the active confor- cological data, and a linear combination of these two mation, and the proper active conformation can only be sets of data is constructed using a partial least squares extracted from the crystal structure of the complex of (PLS) algorithm. Cross-validated and non-cross- the drug molecule and its binding receptor [12–13]. validated r2-values are determined based on the PLS There are mainly two lower conformations for these results in order to validate the predictive properties of compounds (Fig. 1), conformation I referred to the the model. The r2-values can be optimized by itera- amino group close to ring position 6 and conformation tively varying the alignment rules, conformations and II related to the amino group trans to the phenyl ring. other parameters inherent to the technique. Energy comparison showed that conformation I was In this paper, the 3D-QSAR models of 90 phen- more stable than conformation II. To better understand ylalkylamines were established by CoMFA method. the activities of these compounds, the both conforma- This general procedure has been used in the present tions were used to build the models. The crystal con- study to gain insight into the steric and the electrostatic formation of DOET is similar to conformation I. The properties of these hallucinogenic phenylalkylamines, second conformation was acquired by interchange the their influence on the activity and to derive predictive positions of amino group and the methyl group 3D-QSAR models for discovery and prediction of the (amphetamines) or hydrogen atom (phenylethylam- hallucinogenic activities of new analogs for this class of ines). Partial atomic charges were assigned to each hallucinogens. atom and then energy minimization of each molecule was performed using Powell method and Tripos stan- dard force field with a distance-dependent dielectric Data set and methodology function. The minimization was terminated when the energy gradient convergence criterion of 0.005 kcal/ Biological data mol was reached or when the 2000-step minimization cycle limit was exceeded. The structures of 90 phenylalkylamine compounds and Molecular alignment is considered as one of the the biological activities data were cited from the ref- most sensitive parameters in CoMFA analysis [14]. erence [5]. This biological data were collected by The quality and the predictive ability of the model are Shulgin and co-workers. The reported work was about directly dependent on the alignment rule. Once the the hallucinogenic effect on human (oral activity data) active conformation was determined, pharmacophore and it has been considered as a benchmark in QSAR or common substructure alignment was carried out studies. The activities (in Mescaline units) were the according to some rules. In this paper, common sub- ratio of the effective dose of mescaline (350 mg) to the structure alignment was carried out using database mean of the threshold dose of the trial drug and the alignment tool with compound DOB as the template dose required to obtain the full effect. In the following molecule (Fig. 2). To refine the superimposition, some discussion, the alphabet A stands for the relative bio- molecules were manually adjusted using the rotation logical activity, Logarithm of A (log A) was applied in tools. Alignment of all compounds was shown in Fig. 3. the process of modeling. The structures and activity data of all the compounds were sorted by their struc- CoMFA analysis ture character and were listed in Tables 1a, b and c, respectively. Eighteen compounds were randomly In 3D-QSAR analysis, all aligned molecules were put selected as test set marked with asterisks in the tables. into a 3D cubic lattice that extending at least 0.4 nm beyond the volumes of all investigated molecules on all Molecular structure building and alignment axes. The region was partitioned into hundreds of grids with certain grid spacing. In the CoMFA analysis, All computational studies were performed by the Lennard-Jones 6–12 and Coulomb potentials were molecular modeling package sybyl 7.1 (Tripos Inc., employed to calculate the CoMFA steric and 123 J Comput Aided Mol Des (2007) 21:145–153 147 Table 1 Structure and hallucinogenic activity of (a) Phenylethylamines, (b) amphetamines and (c) some specially substituted compounds No Designation R A Log A (a) Phenylethylamines [5] 1 Mescaline 3,4,5-trimethoxy 1 0.00 2ME* 3-ethoxy-4, 5-dimethoxy 1 0.00 3 E 3,5-dimethoxy-4-ethoxy 6 0.78 4 P 3,5-dimethoxy-4-propoxy 7 0.85 5 ASB 3,4-diethoxy-5-methoxy 1.3 0.11 6 2C-E 2,5-dimethoxy-4-ethyl 18 1.26 7 2C-D 2,5-dimethoxy-4-methyl 8 0.90 8 3-TM 3,4-dimethoxy-5-methylthio 4 0.60 9 TM 3,5-dimethoxy-4-methylthio 10 1.00 10 3-TME 3,4-dimethoxy-5-ethylthio 4 0.60 11 4-TME 3-ethoxy-4-methylthio-5-methoxy 4 0.60 12 3-TE* 3-methoxy-4-ethoxy-5-methylthio 4 0.60 13 4-TE 3,5-dimethoxy-4-ethylthio 12 1.08 14 3-TASB 3-ethylthio-4-ethoxy-5-methoxy 2 0.30 15 4-TASB 3-ethoxy-4-ethylthio-5-methoxy 4 0.60 16 5-TASB* 3,4-diethoxy-5-methylthio 2 0.30 17 TP 3,5-dimethoxy-4-propylthio 16 1.20 18 TB 3,5-dimethoxy-4-butylthio 3 0.48 19 2C-G 2,5-dimethoxy-3,4-dimethyl 11 1.04 20 2C-T-F* 2,5-dimethoxy-4-(2-fluoroethylthio) 29 1.46 21 2C-T-13 2,5-dimethoxy-4-(2-methoxyethylthio) 9